Assessing long-term and rare adverse effects of medicines

Abstract

Clinical studies in the development of new medicines are primarily designed to investigate efficacy. Knowledge of adverse effects is therefore limited at the time of approval of new medicines. In this thesis several studies were conducted to investigate long-term and rare adverse effects of medicines. First, the number of patients studied prior to the approval of new medicines licensed in the EU between 2000 and 2010 was investigated, together with the duration of use in pre-approval trials. The results of this study show clearly the limitations of pre-approval trials and highlight the importance of continuous pharmacovigilance and benefit-risk assessment. In recent years, regulatory authorities and pharmaceutical companies increasingly use Risk Management Plans to facilitate this process. Two studies were conducted to determine the value of RMPs, In the first study, it was investigated what the rate was at which safety concerns for medicines included in RMPs at the time of licensing became resolved. In addition we studied how many new safety concerns were added to the RMPs after licensing. After five years of follow-up approximately 20% of safety concerns were resolved, but an equally large number of new concerns was added. In the second study, the potential risk for cancer associated with approved medicines as included in the RMP was investigated. Of the investigated products, 38% (18/48) was associated with a potential risk for cancer. For the vast majority of products additional studies were planned to be conducted (89%). While additional studies were frequently planned to investigate these concerns, their added value appears to be modest as more often other sources of information provided evidence on the cancer risks before new evidence was generated by the studies initially agreed. Two causal studies were conducted investigating long-term adverse effects. The first investigated the relationship between long-term use of 5-alpha reductase inhibitors and the risk for male breast cancer. The second studied long-term use of low-dose aspirin and the risk for neovascular age-related macular degeneration. Both studies’ results showed no increased risks. Finally, two methodological studies were conducted. In the first study, the replicability of observational studies published in the literature was assessed. The results showed that the description of study methodology in published articles is insufficient to allow for studies to be replicated. The last study in the thesis investigates the use of age-matching in case-control studies. Two-thirds of case-control studies published in the literature use matching on age. How this matching is operationalized is often unclear. Inexact matching on age is shown to introduce bias.